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Causes and pathogenesis of galactosemia
Last reviewed: 04.07.2025
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Galactosemia type I
An autosomal recessive disorder associated with mutations in the galactose-1-phosphate uridyltransferase (GALT) gene. The GALT gene is mapped to 9p13. To date, more than 180 different mutations have been described, mostly missense mutations. The most common are the Q188R and K285N mutations, which together account for more than 70% of all mutant alleles in European populations and cause the development of the classic form of galactosemia. A large number of both intra-intron and intra-exonic nucleotide substitutions have also been described in the GALT gene, the presence of which, alone or in various combinations with mutant alleles, can affect the residual activity of the enzyme. One of the most studied intragenic substitutions is the N314D mutation, the so-called Duarte variant. The presence of N314D alone, even in a homozygous state, does not usually lead to the development of the disease, but it does change the level of enzyme activity. The combinations N314D/normal allele and N314D/Q188R cause 75 and 25% of normal enzyme activity, respectively. The frequency of the N314D allele among healthy individuals in various populations is, according to literature data, 6-8%.
Galactosemia type II
The disease is inherited in an autosomal recessive manner. Mutations in the GK1 gene, mapped to 17q24, have been described in most patients, including the P28T mutation found in gypsies.
Galactosemia type III
The disease is inherited in an autosomal recessive manner. The UDP-galactose-4-epimerase (GALE) gene is mapped to chromosome 1p36. Several mutations have been described, including the V94M mutation, which is associated with a severe form of the disease.
Pathogenesis of galactosemia
Galactosemia type I
Galactose-1-phosphate uridyltransferase, along with other enzymes involved in galactose metabolism - galactokinase and galactoepimerase - converts galactose, which is part of milk sugar, into glucose. The consequence of galactose-1-phosphate uridyltransferase deficiency is the accumulation of galactose and galactose-1-phosphate. These substances have a toxic effect on the metabolism of many tissues - the brain, liver, kidneys, and intestines. One of the manifestations of toxicity syndrome is the inhibition of the bactericidal activity of leukocytes, which contributes to the development of sepsis. Hyperchloremic acidosis can be caused by both intoxication accompanied by renal-tubular dysfunction and occur secondarily due to chronic gastrointestinal disorders.
Galactitol and galactonate accumulate in tissues along with galactose-1-phosphate. The development of cataracts in galactose-1-phosphate uridyl transferase deficiency is due to the accumulation of galactitol. The insufficient effectiveness of a galactose-free diet in type I galactosemia is explained by the mechanism of self-intoxication of patients, including the constant biosynthesis of galactose (from glucose) due to the formation of galactose-1-phosphate from uridine diphosphogalactose. A decrease in the concentration of uridine diphosphogalactose disrupts the synthesis of galactosides; this may be the cause of neurological disorders.
Galactosemia type II
When the enzyme is deficient, the galactose phosphorylation stage is disrupted. Cataracts occur as a result of the accumulation of galactotitol in the lens, which disrupts the structure of its fibers and leads to protein denaturation.
Galactosemia type III
UDP-galactose-4-epimerase, along with other enzymes - galactokinase and galactose-1-phosphate uridyltransferase - converts galactose, which is part of milk sugar, into glucose. This enzyme is bifunctional and also participates in the interconversion of UDP-N-acetylgalactosamine and UDP-N-acetylglucosamine - important components of polysaccharides and galactolipids. Enzyme deficiency leads to the accumulation of UDP-galactose and galactose-1-phosphate. The pathogenesis of systemic UDP-galactose-4-epimerase deficiency is similar to that in galactosemia, type I, but the toxicity phenomenon is less pronounced.
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